Device for photodynamical therapy of cancer

ABSTRACT

A method and device for photodynamic therapy for treating cancer. The method includes: providing a photodynamic therapeutic device for treating cancer. The provided device includes a plurality of light emitting diodes that are positionable in proximity of a patient&#39;s body and are adapted to provide a light fluence to a lesion area. The method also includes administering an effective dose of a photosensitizer in the lesion area; positioning the device in proximity to the patient&#39;s body; and irradiating the patient&#39;s body.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a reissue application of U.S. Pat. No. 10,195,459,issued Feb. 5, 2019, from U.S. patent application Ser. No. 14/482,432,filed Sep. 10, 2014, which is a Continuation-In-Part of U.S. patentapplication Ser. No. 13/121,552 filed on Mar. 29, 2011, now pending,which is the U.S. national phase entry of PCT Application No.PCT/IL2009/000929 filed on Sep. 29, 2009, now expired, which claims thebenefit of U.S. Provisional Application No. 61/100,767 filed on Sep. 29,2008. Each of these applications is hereby incorporated by reference inits entirety.

FIELD OF THE INVENTION

The present invention relates to a device of photodynamic therapy, and,more specifically, to a device adapted for photodynamic treating theembraceable body regions.

BACKGROUND OF THE INVENTION

Photodynamic therapy (PDT) is also called photoradiation therapy,phototherapy, or photochemotherapy. It was first used to treat cancerover 100 years ago. It is treatment that uses drugs, calledphotosensitizing agents, along with light to kill cancer cells. Thedrugs only work after they have been activated or “turned on” by certainkinds of light. Depending on the part of the body being treated, thephotosensitizing agent is taken orally, injected into the bloodstream orput on the skin. After the drug is absorbed by the cancer cells, lightis applied only to the area to be treated. The light causes the drug toreact with oxygen, which forms a chemical that kills the cancer cells.PDT may also work by destroying the blood vessels that feed the cancercells and by alerting the immune system to attack the cancer.

The period of time between when the drug is given and when the light isapplied is called the drug-to-light interval. It can be anywhere from acouple of hours to a couple of days and depends on the drug used.

PDT can be used to treat some cancers, or conditions that may developinto a cancer if not treated (precancerous). It is used when theaffected area or the cancer is on or near the lining of internal organs.This is usually with cancers or conditions that affect: the skin, thebreast, the head, the neck, the mouth, the lung, the gullet(oesophagus), the stomach, the rectum and the bile ducts.

Breast cancer affects one in eight women during their lives. Breastcancer kills more women in the United States than any cancer except lungcancer. No one knows why some women get breast cancer, but there are anumber of risk factors. Risks that you cannot change include (a) age;the chance of getting breast cancer rises as a woman gets older; (b)genes; there are two genes, BRCA1 and BRCA2 that greatly increase therisk; women who have family members with breast or ovarian cancer maywish to be tested; (c) personal factors; beginning periods before age 12or going through menopause after age 55.

Other risks include being overweight, using hormone replacement therapy,taking birth control pills, drinking alcohol, not having children orhaving a first child after age 35 or having dense breasts.

Symptoms of breast cancer may include a lump in the breast, a change insize or shape of the breast or discharge from a nipple. Breast self-examand mammography can help find breast cancer early when it is mosttreatable. Treatment may consist of radiation, lumpectomy, mastectomy,chemotherapy, and hormone therapy.

Breast cancer recurrences after mastectomy pose a therapeutic challengewith few surgical options. If disease is localized, surgical excisioncan be attempted. However, these lesions often are widespread throughoutthe chest wall or involve heavily irradiated tissue. Many patients havereceived aggressive chemotherapy with little to no local response andhave exhausted most avenues for local control. Multiple studies showthat photodynamic therapy (PDT) provides good tumor kill for primarycutaneous malignancies and suggest its effectiveness in ablating dermallymphatic recurrences of breast cancer. Food and Drug Administration(FDA) approved uses for PDT include lung and esophageal lesions, buttreatment of bladder, head and neck, and other tumor sites with novelapproaches has been reported. PDT exploits the accumulation ofphotosensitizers into the tumor, which then is locally excited withvisible light. Selectivity of treatment comes from the excretion of drugfrom normal tissue over time, promoting a concentration gradient withinthe tumor plus the location of the activating light. Treatment depthvaries with the wavelength of light that activates the sensitizer used.The singlet oxygen that is produced during the transfer of energy fromlight source to drug disrupts plasma, nuclear, and mitochondrial cellmembranes, resulting in apoptosis. Local edema and perivascular stasisoccur rapidly, within hours of treatment. Tumor necrosis can be evidentwithin 2 to 24 hours. Photofrin (dihematoporphyrin ether; AxcanScandipharm, Birmingham, Ala.) is the only FDA-approved photosensitizeravailable for the treatment of cancer. The light source used to activatePhotofrin (630 nm) is topically delivered via lasers by using diffusingcatheters and is focused on skin surfaces by using a microlens. Thismodality has been previously reported in a small number of breast cancerpatients with chest wall recurrence, with good responses.

U.S. Pat. No. 6,899,723 ('723) discloses methods and compounds for PDTof a patient's target tissue, using a light source that preferablytransmits light to a treatment site transcutaneously. The methodprovides for administering to the subject a therapeutically effectiveamount of a targeted substance, which is either a targetedphotosensitizing agent, or a photosensitizing agent delivery system, ora targeted prodrug. This targeted substance preferably selectively bindsto the target tissue. Light at a wavelength or waveband corresponding tothat which is absorbed by the targeted substance is then administered.The light intensity is relatively low, but a high total fluence isemployed to ensure the activation of the targeted photosensitizing agentor targeted prodrug product. Transcutaneous PDT is useful in thetreatment of specifically selected target tissues, such as vascularendothelial tissue, the abnormal vascular walls of tumors, solid tumorsof the head and neck, tumors of the gastrointestinal tract, tumors ofthe liver, tumors of the breast, tumors of the prostate, tumors of thelung, nonsolid tumors, malignant cells of the hematopoietic and lymphoidtissue and other lesions in the vascular system or bone marrow, andtissue or cells related to autoimmune and inflammatory disease.

In accordance with '723, method of therapeutically treating a targettissue provides destroying or impairing target cell by the specific andselective binding of a photo sensitizer agent to the target tissue,cell, or biological component. At least a portion of the target tissueis irradiated with light at a wavelength or waveband within acharacteristic absorption waveband of the photosensitizing agent. It iscontemplated that an optimal total fluence for the light administered toa patient is determined clinically, using a light dose escalation trial.The total fluence administered externally during a treatment preferablyis in the range from 500 Joules to 70,000 Joules.

It should be emphasized that according data published by the US NationalCancer Institute, maximal penetration depth achievable for photodynamictherapy is about 1 cm. Practically, depth penetration available forreliable photodynamic therapy can be performed at the penetration depthof 2-3 mm. Providing a photodynamic therapy generating high-energy lightfluence characterized by greater depth of radiation penetration intotissues of the patient's body is an unmet and long-felt need.

SUMMARY OF THE INVENTION

It is hence one object of the invention to disclose a method ofphotodynamic therapy for treating cancer. The aforesaid method comprisesthe steps of (a) providing a photodynamic therapeutic device fortreating cancer; said device comprises a plurality of light emittingdiodes positionable in proximity of a patient's body adapted to providea light fluence to a lesion area and cooling means; (b) administering aneffective dose of a photosensitizer in a lesion area of said patient'sbody; (c) positioning the device in proximity of said device to saidpatient's body; (d) irradiating said patient's body.

It is a core purpose of the invention to provide the step of irradiatingsaid lesion area which is characterized by power density ranging between1 mW/cm² and 10,000 mW/cm² and treatment duration ranging between 150sec and 3600 sec such that density of total energy incident to saidlesion area is in a range between 0.01 1 J/cm² and 100 J/cm², thereatsaid step of irradiating said patient's body is performed by saidphotodynamic therapeutic device having a luminous surface of an areawhich is greater than 10 cm².

A further object of the invention is to disclose the device positionedin proximity of said patient's body in a location selected from thegroup consisting of a breast, an arm, a leg, a neck, an abdomen and anycombination thereof.

A further object of the invention is to disclose a mode of deviceoperation is selected from the group consisting of a continuous mode, apulse mode, an intermittent mode and any combination thereof.

A further object of the invention is to disclose the step of positioningthe device in proximity of said patient's body further comprising a stepof preliminary positioning a silicon spacer therebetween.

A further object of the invention is to disclose the step of irradiatingat maximum light intensity at at least one wavelength selected from thegroup consisting of: a wavelength of about 630 nm performed incoordination with said preceding step of administering an effective doseof a photosensitizer 5-aminolaevulinic acid (5-ALA); a wavelength ofabout 585 to about 740 nm performed in coordination with said precedingstep of administering an effective dose of a photosensitizer5,10,15,20-tetrakis(m-hydroxyphenyl) chlorin (Foscan); a wavelength ofabout 570 to about 670 nm is performed in coordination with saidpreceding step of administering an effective dose of a photosensitizermethyl aminolevulinate (Metvix); a wavelength of about 615 to about 800nm performed in coordination with said preceding step of administeringan effective dose of a photosensitizer Pd-bacteriopheophorbide (Tookad);a wavelength of about 600 to about 750 nm performed in coordination withsaid preceding step of administering an effective dose of aphotosensitizer concentrated distillate of hematoporphyrins (Photofrin);a wavelength of about 450 to about 600 nm performed in coordination withsaid preceding step of administering an effective dose of aphotosensitizer verteporfin (Visudyne) and any combination thereof.

A further object of the invention is to disclose the step of irradiatingperformed by said plurality of emitting diodes distributed along aninner surface of an annular structure.

A further object of the invention is to disclose the step of irradiatingperformed by LEDs grouped in a plurality of cooled units comprising atleast two diodes; said cooled units are distributed along said innersurface of said annular structure.

A further object of the invention is to disclose the step of positioningsaid device in proximity of said patient's breast further comprising astep of adjusting a length of said annular structure according to apatient's breast size.

A further object of the invention is to disclose the step of positioningsaid device in proximity of said patient's breast further comprisingsteps of disposing said patient on a bearing surface in a prone positionand putting in said patient's breast in said annular structure so thatsaid annular structure embraces thereof and/or positioning the device inproximity of said patient's breast is performed frontally.

A further object of the invention is to disclose the light intensitygradually increasing over treatment time, allowing each measure of depthto receive an effective amount of light until that depth is treated.

A further object of the invention is to disclose a device forphotodynamic therapy for treating cancer. The aforesaid device comprisesa plurality of light emitting diodes postionable in proximity of apatient's body adapted to provide a light fluence to a lesion area andcooling means.

It is a core purpose of the invention to provide the device having aluminous surface positioned in proximity of the patient's body part tobe treated and having an area which is greater than 10 cm².

A further object of the invention is to disclose the device configuredfor irradiating said lesion area is characterized by power densityranging between 1 mW/cm² and 10,000 mW/cm² and treatment durationranging between 150 sec and 3600 sec such that density of total energyincident to said lesion area is in a range between 0.01 1 J/cm² and 100J/cm².

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may beimplemented in practice, a plurality of embodiments is adapted to now bedescribed, by way of non-limiting example only, with reference to theaccompanying drawings, in which

FIG. 1 is an isometric view of the LED unit;

FIG. 2 is an isometric view of the photodynamic therapeutic device;

FIG. 3 is an isometric view of the photodynamic therapeutic deviceattached to the patient's breast;

FIG. 4 is a side view of the alternative embodiment of the photodynamictherapeutic device attached to the patient's breast;

FIG. 5 is a front view of the alternative embodiment of the photodynamictherapeutic device attached to the patient's breast;

FIG. 6 is a schematic diagram of the photodynamic therapeutic devicelocations on the patient's body;

FIG. 7 is a photo of a remnant fibrous tissue following remission of abreast cancer tumour by photodynamic therapy;

FIG. 8 is a graph of light intensity dependence on penetration depthwithin chicken breast;

FIG. 9 shows graphs of irradiance and fluence rate depending on luminousarea; and

FIGS. 10a, 10b, 11a, 11b, 12a, and 12b schematically show propagation oflight irradiated by LED matrices of different dimensions.

DETAILED DESCRIPTION OF THE INVENTION

The following description is provided, alongside all chapters of thepresent invention, so as to enable any person skilled in the art to makeuse of said invention and sets forth the best modes contemplated by theinventor of carrying out this invention. Various modifications, however,are adapted to remain apparent to those skilled in the art, since thegeneric principles of the present invention have been definedspecifically to provide a photodynamic therapeutic device and a methodof using thereof.

The term ‘photodynamic therapy (PDT)’ hereinafter refers to therapy thatuses laser, or other light emitting diodes, combined with alight-sensitive drug (sometimes called a photosensitizing agent) todestroy cancer cells.

The term ‘lesion area’ hereinafter refers to an area of internalcancerated tissues to be treated. The power and energy density values inthe present invention relate to the aforesaid lesion area.

LED arrays employed as a light source during photodynamic therapy (PDT)can extend the effective penetration for light delivery so that it maybe applied to treatment of tumours at depths of more than onecentimeter. Tumour range Enhancement that could be treated by PDT isbeyond the current methods providing one centimeter PDT accessibility.

The hypothesis is that a powerful water cooled LED array that canachieve sufficient light levels through more than one centimeter ofmammary tissue that activate photosensitizer effectively to cause tumourcell death in a syngeneic mouse model of breast cancer.

LEDs are a more recent light delivery system with wavelength specificityand high fluence rates. The cooling system enables the delivery ofextremely high fluence rates without risk of thermal damage due to theheat output of the LED arrays. This system allows external exposure toextremely high light levels and takes advantage of scattering to deliversufficient light to activate photo sensitizer to tissue depths notaccessible to current light delivery systems.

A photosensitizing agent is a drug that makes cells more sensitive tolight. Once in the body, the drug is attracted to cancer cells. It doesnot do anything until it is exposed to a particular type of light. Whenthe light is directed at the area of the cancer, the drug is activatedand the cancer cells are destroyed. Some healthy, normal cells in thebody will also be affected by PDT, although these cells will usuallyheal after the treatment.

About 5% to 19% of breast cancer patients suffer from chest wallrecurrences after mastectomy, and these breast cancer recurrences have ahigh impact on physical and psychological well-being. Although surgeryand radiation therapy are standard treatments for chest wall recurrencesafter mastectomy, PDT shows promise in treating these patients,according to the researchers.

Reference is now made to FIG. 1 , presenting an LED unit 35 comprising amatrix of LEDs 30 disposed on a base plate 130. A passage 50accommodating a coolant is attached to the back of the plate 130. Thus,the heat generated by the LEDs 30 is extracted by means of the coolantcirculating in the cooling loop.

Reference is now made to FIG. 2 , showing a PDT device 100 comprising anannular structure 40, LEDs 30 disposed at an inner surface of theaforesaid annual structure 40, the passages 50 accommodating the coolantcirculating through feeding pipes 10 and 20. A strap 80 fixates thestructure 40 on the patient's breast.

Reference is now made to FIG. 3 , presenting the device 100 attached toa patient's breast 70. The light emitted by the LEDs 30 (not shown)propagates into the patient's breast 70 and affects a sensitizerconcentrated in the lesion area. PDT exploits the accumulation ofphotosensitizers into the tumor, which then is locally excited withvisible light. Selectivity of treatment comes from the excretion of drugfrom normal tissue over time, promoting a concentration gradient withinthe tumor plus the location of the activating light. Treatment depthvaries with the wavelength of light that activates the sensitizer used.The singlet oxygen that is produced during the transfer of energy fromlight emitting diode to drug disrupts plasma, nuclear, and mitochondrialcell membranes, resulting in apoptosis. Local edema and perivascularstasis occur rapidly, within hours of treatment.

The proposed device creates high light intensity in the lesion area toprovide required light fluence in shorter period of time. The heatgenerated by the LED is extracted by the coolant circulating in thepassages 50. The proposed arrangement allows safely attaching highintensity light emitting diode to the patient's body.

Reference is now made to FIGS. 4 and 5 , shown side and front views ofan alternative embodiment 200 of the PDT device, respectively. Theconfiguration of the device 200 is conformed to a form of the patient'sbreast 70. The light units 35 are tilted relative to an annularstructure 120. Adjustment of a length of the annular structure 120according to a size of the patient's breast 70 is in a scope of thecurrent invention.

Reference is now made to FIG. 6 , presenting optional body locationswhere the proposed therapeutic device can be attached. The therapeuticdevices are attached to the patient's body 250 at a neck 260 (300a), anarm 270 (300b and 300c), a leg 280 (300d and 300e) and abdomen 290(300f).

In accordance with one embodiment of the current invention, aphotodynamic therapeutic device for treating cancer comprises at leastone light emitting diode attachable to a patient's body adapted toprovide an effective fluence to a lesion area. The aforesaid devicefurther comprises an annular structure embracing the patient's body anda passage connectable to a cooling loop providing a circulative coolantinto the passage. The light emitting diode is secured to an innersurface of the structure. The coolant accommodated in the passage isadapted for removing heat generated by the light emitting diodes. Theannular embracing structure has 5 Rebel LEDs per cm. Each rebel yields700 mw of light power. The aforesaid structure provides total of 3500 mwper cm². The LEDs have the means for internal cooling of the LEDs.

The used LED (Rebel by Phillips) is 100 times more powerful and has athermal heat pad area common in the prior art while we keep theoperating temperature under 50 degrees C.

Our research has shown that when a light emitting diode is wrappedaround the breast that the light that is available at the center of thebreast is a summation of the light that comes from each of the segmentssurrounding the breast.

90 degrees of light around a breast would yield ¼ of the fluence at thecenter of a breast to that which is 360 degrees (this results in 4× thelight fluence) and probably adds an additional 1-2 cm of additionalbreast penetration depth. This is only important effect when the lightfluence is high enough at the surface.

An example: 15 segments would be required to surround the breast due tothe circumference of the breast (15″) and the size of each segment (1″).

The flexible “annular structure” comprises 5 to 15 small platforms orsegments (hereafter referred to as segments) that are coupled togetherby a mechanical linkage of some type (fabric, Velcro, flexible material(silicone, ect. . . . )). Each one of the segments is small enough tocover some area say 2.5 cm×2.5 cm to say 4 cm×4 cm.

Each one of the segments is not flexible, because the very high heatremoval that is required to keep the LEDs cool.

Each segment would contain 2 to 40 high power LEDs and would require upto 100 watts of heat removal for each segment.

Each segment would contain a 0.005″ thick circuit board with direct LEDsoldered contact copper to a liquid heat removal chamber with turbulentliquid flow to remove the maximum heat from the segment.

Each one of the segments would have a clear silicone spacer mat 0.3-0.5cm thick directly in front of the LEDs to protect and to remove thepossibility of the lens of the LED directly coming into contact with theskin and causing direct heat transfer.

A tumor requires an extremely large fluence (10,000 mW/cm²) at thesurface of a breast to have enough light “effective fluence” (50 mW/cm²)to activate the drug to treat the tumor at a distance 4 cm into thebreast tissue. I think that until our patent these type of light levelsdescribed in various patents by many inventors have never been thoughtof for PDT.

According to preclinical investigations performed in mice, the mosteffective dosage resulting in full tissue recovery is characterized bythe following parameters:

Power density ranging between 1 mWcm² and 10,000 mW/cm²;

Treatment duration ranging between 150 sec and 3600 sec;

Total energy density which is incident to the lesion area is in a rangebetween 0.01 1 J/cm² and 100 J/cm².

The interdependence between power density and treatment duration bringswith it limitations in the treatment procedure: Cancer cells exposed toirradiation at a power density lower than 1 mW/cm² are responsive. At apower density greater than 10,000 mW/cm², tissues are likely to undergoburning due to thermal effects. In other words, the aforesaid values oftotal energy density incident on the cancer tissue should be within therange of the energy density limited by the sensibility threshold on thelow density side and tissue burning on the high density side.

Results of preclinical trials are presented in Tables 1 and 2. Table 1depicts a set of experiments on mice. The presented data characterizepower densities and energy densities which are incident on the cancertissue. Treatment durations are also reported. Table 2 provides medicalresults of the experiment. In the column of number of mice with responseto treatment, the first number corresponds to mice with a more than 50%reduction of tumour size following the treatment*. The second number isa total number of samples exposed to a specific light dose.

TABLE 1 Joules Time of Light Intensity at delivered treatment tumorsurface Light dose Joules/cm² Seconds mW/cm² High dose light A 35 300114 Low dose light B 7 60 114 Low dose light C 5 600 8.3 Low dose lightD 0.01 1200 0.83

TABLE 2 Tissue Number of mice thickness** Number of with response toLight dose (cm) treatments treatment* High dose light A 0 1 4/5  Lowdose light B 0 3 8/10 Low dose light C 2 3 4/9  Low dose light D 4 32/10 Control-No light 0 0 0/10 **Tissue thickness refers to a thicknessof pork tissue through which the cancer tumour in the mouse wasirradiated. The dimension of the tumour was larger than 1 cm.

Reference is now made to FIG. 7 , presenting a remnant fibrous tissuefollowing remission of a breast cancer tumour by photodynamic therapyusing the light system of the present invention. There are no tumourcells visible. This figure is representative of the pathology to date inanimals that have displayed remission in this experiment.

Reference is now made to FIG. 8 , presenting experimental dataconcerning intensity profile depending on a penetration depth. It isshown that the penetration depth increases with extension of luminancebody. As it appears from FIG. 8 , 1 cm² luminance body provides powerdensity 0.2 mW/cm² at penetration depth of about 4 cm, while the samepower density is obtained at the penetration depth of about 8 cm with a100 cm² luminance body.

Reference is now made to FIG. 9 , presenting graphs of irradiance andfluence rate depending on luminous area. The irradiance and fluence ratecurves were measured at fixed penetration depth. Pursuant to graphcomparison, a most effective LED arrangement has the luminous surfacegreater than about 10 cm².

In Table 3, the first row corresponds to the luminous area with LEDsthat were used in chicken breast experiment while the rest of the rowsprovide model treatment protocol applicable to human.

TABLE 3 1.875 LEDs/cm2 Mouse Study LEDs 3.75 W/cm2 LED power Kilojoulesdelivered in cm (X) cm (Y) cm2 Kilowatts eff. @ 10% 60 s 3600 s (1 hr)Applications 10 16  160 0.60 0.060 0.004 0.2 Panel 35 10  350 1.31 0.1310.008 0.5 14″ × 4″ Arm 50 10  500 1.88 0.188 0.011 0.7 20″ × 4″ Thigh 9010  900 3.38 0.338 0.020 1.2 36″ × 4″ Waist 90 15 1350 5.06 0.506 0.0301.8 36″ × 6″ Waist 110  15 1650 6.19 0.619 0.037 2.2 43″ × 6″Waist/Chest 130  15 1950 7.31 0.731 0.044 2.6 51″ × 6″ Waist/Chest

Similar to the previous table 3, in table 4, the first row correspondsto a luminous area with more powerful LEDs then that were used inchicken breast experiment. It should be emphasized that, geometricconfiguration of the device for photodynamic therapy is adapted for aspecific tumour location in the patient's body.

TABLE 4 Today's LEDs capability 1.875 LEDs/cm2 Kilojoules 3.75 W/cm2 LEDpower delivered in cm (X) cm (Y) cm2 Kilowatts eff. @ 25% 60 s 3600 s (1hr) Applications 10 16  160 0.60 0.150 0.009 0.5 Panel 35 10  350 1.310.328 0.020 1.2 14″ × 4″ Arm 50 10  500 1.88 0.469 0.028 1.7 20″ × 4″Thigh 90 10  900 3.38 0.844 0.051 3.0 36″ × 4″ Waist 90 15 1350 5.061.266 0.076 4.6 36″ × 6″ Waist 110  15 1650 6.19 1.547 0.093 5.6 43″ ×6″ Waist/Chest 130  15 1950 7.31 1.828 0.110 6.6 51″ × 6″ Waist/Chest

In Tables 5 and 6, estimated data concerning exposure doses provided toplurality of tumour locations by LED matrices of different LED packingdensity (1.875 LED/cm² and 10 LED/cm², respectively), The modern LEDmeans provide an option of short pulse mode of the photodynamic therapy.

TABLE 5 1.875 LEDs/cm2 Future LEDs potential 3.75 W/cm2 LED powerKilojoules delivered in cm (X) cm (Y) cm2 Kilowatts eff. @ 50% 60 s 3600s (1 hr) Applications  10 16  160 0.60 0.300 0.018 1.1 Panel  35 10  3501.31 0.656 0.039 2.4 14″ × 4″ Arm  50 10  500 1.88 0.938 0.056 3.4 20″ ×4″ Thigh  90 10  900 3.38 1.688 0.101 6.1 36″ × 4″ Waist  90 15 13505.06 2.531 0.152 9.1 36″ × 6″ Waist 110 15 1650 6.19 3.094 0.186 11.1 43″ × 6″ Waist/Chest 130 15 1950 7.31 3.656 0.219 13.2  51″ × 6″Waist/Chest

TABLE 6 10 LEDs/cm2 Future LEDs potential 20 W/cm2 LED power Kilojoulesdelivered in cm (X) cm (Y) cm2 Kilowatts eff. @ 50% 60 s 3600 s (1 hr)Applications  10 16  160  3.20  1.600 0.096  5.8 Panel  35 10  350  7.00 3.500 0.210 12.6 14″ × 4″ Arm  50 10  500 10.00  5.000 0.300 18.0 20″ ×4″ Thigh  90 10  900 18.00  9.000 0.540 32.4 36″ × 4″ Waist  90 15 135027.00 13.500 0.810 48.6 36″ × 6″ Waist 110 15 1650 33.00 16.500 0.99059.4 43″ × 6″ Waist/Chest 130 15 1950 39.00 19.500 1.170 70.2 51″ × 6″Waist/Chest

Reference is now made to FIGS. 10 (a and b), 11 (a and b) and 12 (a andb), presenting schematically operative principle of the presentinvention and. FIG. 10 shows a matrix of N×N LEDs 30, while FIGS. 11 and12 correspond to LED matrices of M×M and K×K, respectively, thereatN<M<K.

It should be appreciated that there is a limitation of density of lightintensity administered to the patient's body. The intensive narrow laserbeam causes a burn. Consequently, a penetration depth of light used forphotodynamic treatment is also limited according to Beer's law.

According to the present invention, an illuminated area of the patient'sbody 310 is two-dimensional. A growing number of side LEDs on aperimeter of the LED matrix also contribute into the resultant intensityin the target volume of a tumour 320. Light rays 330 originated fromside LEDS reach the tumour 320. As seen in FIGS. 10b, 11b and 12b, thepenetration depth grows with the matrix dimension. The describedpresentation is experimentally proved (see FIGS. 8 and 9 ).Specifically, in the model experiments on chicken breast, increase inthe penetration depth from 4 cm up to 8 cm has been achieved.

An intermittent operation mode of the device is in the scope of thecurrent invention. Intermitting active and inactive phases ofillumination increases the performance of the drug because allows forcooling the skin during inactive phases to reduce heating effect ofcontinuous light.

Some embodiments of the invention utilise a coolant loop that is inseries with each segment of LEDs. The series configuration reduces waterflow with increased resistance and the last segments will be the hottestdepending on flow rate. The aforementioned is taken into considerationduring the planning of the treatment schedule.

A parallel coolant loop is also contemplated in some embodiments of theinvention where greater flow rates and possibly more consistently lowertemperatures are required. The parallel configuration is defined by anarrangement of the invention whereby fluid enters all segments at thesame time and leaves from all segments into a larger return tube.

In some embodiments of the invention ultimate control on the lightoutput of the LEDs on each segment is provided: the output power to theunit may be altered in 0.1% steps from 0-100%

It is another objective of the invention to disclose treatment protocolsfor slowly raising the power level over the treatment area.

This might be important since as one penetrates a deep area, the closestflesh to the LED segment might receive a too powerful dosage and reducedrug effectiveness. On the other hand, a continuous low output may notachieve the depth of treatment. An optimal treatment protocol may be togradually increase the light output over treatment time, allowing eachmeasure of depth to receive the right amount of light until that depthis treated. Light is increased for deeper penetration in staged lightincreases.

In accordance with the current invention, a method of photodynamictherapy for treating cancer is disclosed. The aforesaid method comprisesthe steps of (a) providing a photodynamic therapeutic device fortreating cancer; said device comprises a plurality of light emittingdiodes positionable in proximity of a patient's body adapted to providea light fluence to a lesion area and cooling means; (b) administering aneffective dose of a photosensitizer in a lesion area of said patient'sbody; (c) positioning the device in proximity of said device to saidpatient's body; (d) irradiating said patient's body.

It is a core feature of the invention to provide the step of irradiatingsaid lesion area which is characterized by power density ranging between1 mW/cm² and 10,000 mW/cm² and treatment duration ranging between 100sec and 3600 sec such that density of total energy incident to saidlesion area is in a range between 0.01 1 J/cm² and 100 J/cm², thereatsaid step of irradiating said patient's body is performed by saidphotodynamic therapeutic device having a luminous surface of an areawhich is greater than 10 cm².

In accordance with a further embodiment of the current invention, thedevice positioned in proximity of said patient's body in a location isselected from the group consisting of a breast, an arm, a leg, a neck,an abdomen and any combination thereof.

In accordance with a further embodiment of the current invention, a modeof device operation is selected from the group consisting of acontinuous mode, a pulse mode, an intermittent mode and any combinationthereof.

In accordance with a further embodiment of the current invention, thestep of positioning the device in proximity of said patient's bodyfurther comprises a step of preliminary positioning a silicon spacertherebetween.

In accordance with a further embodiment of the current invention, thestep of irradiating at maximum light intensity at at least onewavelength is selected from the group consisting of: a wavelength ofabout 630 nm performed in coordination with said preceding step ofadministering an effective dose of a photosensitizer 5-aminolaevulinicacid (5-ALA); a wavelength of about 585 to about 740 nm performed incoordination with said preceding step of administering an effective doseof a photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl) chlorin(Foscan); a wavelength of about 570 to about 670 nm is performed incoordination with said preceding step of administering an effective doseof a photosensitizer methyl aminolevulinate (Metvix); a wavelength ofabout 615 to about 800 nm performed in coordination with said precedingstep of administering an effective dose of a photosensitizerPd-bacteriopheophorbide (Tookad); a wavelength of about 600 to about 750nm performed in coordination with said preceding step of administeringan effective dose of a photosensitizer concentrated distillate ofhematoporphyrins (Photofrin); a wavelength of about 450 to about 600 nmperformed in coordination with said preceding step of administering aneffective dose of a photosensitizer verteporfin (Visudyne) and anycombination thereof.

In accordance with a further embodiment of the current invention, thestep of irradiating is performed by said plurality of emitting diodesdistributed along an inner surface of an annular structure.

In accordance with a further embodiment of the current invention, thestep of irradiating is performed by LEDs grouped in a plurality ofcooled units comprising at least two diodes; said cooled units aredistributed along said inner surface of said annular structure.

In accordance with a further embodiment of the current invention, thestep of positioning said device in proximity of said patient's breastfurther comprises a step of adjusting a length of said annular structureaccording to a patient's breast size.

In accordance with a further embodiment of the current invention, thestep of positioning said device in proximity of said patient's breastfurther comprises steps of disposing said patient on a bearing surfacein a prone position and putting in said patient's breast in said annularstructure so that said annular structure embraces thereof and/orpositioning the device in proximity of said patient's breast isperformed frontally.

In accordance with a further embodiment of the current invention, thelight intensity gradually increases over treatment time, allowing eachmeasure of depth to receive an effective amount of light until thatdepth is treated.

In accordance with a further embodiment of the current invention, adevice for photodynamic therapy for treating cancer is disclosed. Theaforesaid device comprises a plurality of light emitting diodespostionable in proximity of a patient's body adapted to provide a lightfluence to a lesion area and cooling means.

It is a core feature of the invention to provide the device having aluminous surface positioned in proximity of the patient's body part tobe treated and having an area which is greater than 10 cm².

In accordance with a further embodiment of the current invention, thedevice is configured for irradiating said lesion area is characterizedby power density ranging between 1 mW/cm² and 10,000 mW/cm² andtreatment duration ranging between 150 sec and 3600 sec such thatdensity of total energy incident to said lesion area is in a rangebetween 0.01 1 J/cm² and 100 J/cm².

What is claimed is:
 1. A method of photodynamic therapy for treatingcancer; said method comprising the steps of: a. providing a photodynamictherapeutic device for treating cancer;, said device comprises a coppercircuit board, a plurality of light emitting diodes on said coppercircuit board and positionable in proximity of a patient's body adaptedto provide a light fluence to a lesion area and a passage connected tosaid copper circuit board to withdraw heat and accommodating a coolantcirculating within said passage and removing heat generated by saidplurality of light emitting diodes;, wherein said passage is connectedin fluid communication to a feeding pipe; b. administering an effectivedose of a photosensitizer in a lesion area of said patient's body; c.positioning the device in proximity of said lesion area of saidpatient's body, wherein said lesion area has an effective dose of aphotosensitizer administered therein; dc. irradiating said lesion area;ed. transferring heat generated by said plurality of light emittingdiodes through said copper circuit board to said passage; and fe.removing said generated heat from said passage by said coolantcirculating within said passage; wherein said step of irradiating saidlesion area is characterized by power density at a skin surfaceoverlaying the lesion area ranging between 1200 mW/cm² and 10,0003500mW/cm² and treatment duration ranging between 150 sec and 3600 sec suchthat density of total energy incident to said lesion area is in a rangebetween 0.01 J/cm² and 100 J/cm², thereat, wherein said step ofirradiating said lesion area is performed by said photodynamictherapeutic device having a luminous surface of a total area which isgreater than 10from 31.25 cm² to 240 cm².
 2. The method according toclaim 1, wherein said device is positioned in proximity of saidpatient's body in a location selected from the group consisting of abreast, an arm, a leg, a neck, an abdomen and any combination thereof.3. The method according to claim 1, wherein a mode of device operationis selected from the group consisting of a continuous mode, a pulsemode, an intermittent mode and any combination thereof.
 4. The methodaccording to claim 1, wherein said step of positioning the device inproximity of said patient's body lesion area further comprises a step ofpreliminary positioning a silicon spacer between the device and saidpatient's body.
 5. The method according to claim 1, wherein said step ofirradiating said lesion area includes irradiating at maximum lightintensity at at least one wavelength selected from the group consistingand is performed in coordination with the photosensitizer that isadministered within the lesion area and comprises at least one of: awavelength of about 630 nm performed in coordination with said precedingstep of administering an effective dose of a with the photosensitizerbeing 5-aminolaevulinic acid (5-ALA); a wavelength of about 585 to about740 nm performed in coordination with said preceding step ofadministering an effective dose of a with the photosensitizer being5,10,15,20-tetrakis(m-hydroxyphenyl) chlorin (Foscan); a wavelength ofabout 570 to about 670 nm is performed in coordination with saidpreceding step of administering an effective dose of a with thephotosensitizer being methyl aminolevulinate (Metvix); a wavelength ofabout 615 to about 800 nm performed in coordination with said precedingstep of administering an effective dose of a with the photosensitizerbeing Pd-bacteriopheophorbide (Tookad); a wavelength of about 600 toabout 750 nm performed in coordination with said preceding step ofadministering an effective dose of a with said photosensitizer being aconcentrated distillate of hematoporphyrins (Photofrin); or a wavelengthof about 450 to about 600 nm performed in coordination with saidpreceding step of administering an effective dose of a with saidphotosensitizer being verteporfin (Visudyne) and any combinationthereof.
 6. The device method according to claim 1, wherein said step ofirradiating is performed by said plurality of light emitting diodesdistributed along an inner surface of an annular structure.
 7. Themethod according to claim 6, wherein said step of irradiating isperformed by LEDs said plurality of light emitting diodes are grouped ina plurality of cooled units comprising at least two of said plurality oflight emitting diodes; said cooled units are distributed along saidinner surface of said annular structure.
 8. The method according toclaim 1 6, wherein said step of positioning said device in proximity ofsaid lesion area of said patient's body comprises positioning saiddevice in proximity of said patient's breast, and wherein positioningsaid device in proximity of said patient's breast further comprises astep of adjusting a length of said annular structure according to apatient's breast size.
 9. The method according to claim 1 8, whereinsaid step of positioning said device in proximity of said patient'sbreast further comprises steps of disposing said patient on a bearingsurface in a prone position and putting in said patient's breast in saidannular structure so that said annular structure embraces thereof and/orpositioning the device in proximity of said patient's breast isperformed frontally.
 10. The method according to claim 1, wherein atsaid step of irradiating, light intensity gradually increases overtreatment time, allowing each measure of depth to receive an effectiveamount of light until that depth is treated.
 11. The method according toclaim 1, wherein said copper circuit board is 0.005″ thick.
 12. Themethod according to claim 1, wherein said photodynamic therapeuticdevice comprises a plurality of segments.
 13. The method according toclaim 12, wherein each segment contains 2 to 40 high power LEDs andwould require up to 100 watts of heat removal for each segment.
 14. Themethod according to claim 12, wherein said copper circuit boardcomprises a plurality of said copper circuit boards having a pluralityof said plurality of light emitting diodes thereon, and wherein eachsegment contains one of said copper circuit boards.
 15. The methodaccording to claim 12, wherein said segments have a clear siliconespacer mat directly in front of the LEDs to protect and to remove thepossibility of a lens of the LED directly coming into contact with theskin and causing direct heat transfer.
 16. The method according to claim15, wherein said clear silicone spacer mat is 0.3-0.5 cm thick.
 17. Themethod according to claim 15, wherein the LEDs are soldered directly tothe copper circuit board.
 18. The method according to claim 1, whereinsaid coolant is not in direct contact with said light emitting diodes.